This invention relates to a controlled release formulation of a therapeutic agent and in particular to a sustained release formulation, in which the carrier comprises a synergistic effective amount of a hydrocolloid and cellulose ether.
Sustained or slow release compositions containing pharmaceutical medicaments or other active ingredients are designed to contain higher concentrations of the medicament and are prepared in such a manner as to effect sustained or slow release into the gastro-intestinal digestive tract of humans or animals over an extended period of time. Well absorbed oral sustained or slow release therapeutic drug dosage forms have inherent advantages over conventional, immediate release dosage forms. The advantages include less frequent dosing of a medicament and resultant patient regime compliance, a more sustained drug blood level response, the possibility of effecting therapeutic action with less ingested drug and the mitigation of side effects. By providing a slow and steady release of the medicament over time, absorbed drug concentration spikes are mitigated or eliminated by effecting a smoother and more sustained blood level response.
For this purpose a retard formulation has to meet some criteria, namely causing an uniform and constant dissolution and being effective for an extended period of time. It is also important that such a formulation be simple to make and that the manufacturing process be reproducible and be used for a number of different substances.
To prepare sustained release formulations in the form of a solid oral dosage, such as tablets, various hydrophilic polymers have been utilized.
For example, hydroxypropylmethyl cellulose has been used as a polymer for controlled release formulation. For instance, U.S. Pat. Nos. 4,259,341 to Lowey, U.S. Pat. No. 3,870,190 to Lowey, et al., U.S. Pat. No. 4,226,849 to Schor, and U.S. Pat. No. 4,357,469 to Schor relate to the preparation of tablets having a hydrophilic matrix comprised of hydroxypropylmethyl cellulose alone or mixed with other cellulose derivatives. In addition, U.S. Pat. Nos. 4,369,172 and 4,389,393 to Schor, et al. relate to a sustained release formulation in which the carrier associated therewith contains hydroxypropylmethyl cellulose alone or mixed with methyl cellulose and or sodium carboxy methyl cellulose. Sheth in U.S. Pat. Nos. 4,167,448 and 4,126,672 relate to the use of a pharmaceutical composition containing hydroxypropylmethyl cellulose.
Another polymer that has been used in controlled release formulations is xanthan gum.
U.S. Pat. Nos. 5,292,534 and 5,427,799 to Valentine, et al. disclose a sustained release formulation comprising a pharmaceutical e.g., niacin with xanthan gum wherein the xanthan gum is present in 20-50 wt %. of the formulation.
U.S. Pat. No. 5,415,871 to Pankhania, et al. is directed to a sustained release pharmaceutical formulation comprising xanthan gum, a pharmaceutically active ingredient, for example, ibuprofen or flurbiprofen and other optional excipients. In this formulation, the carrier which consists essentially of the xanthan gum is at least 50% xanthan gum by weight. U.S. Pat. No. 5,047,248 to Calanchi also discloses a pharmaceutical composition consisting of a pharmaceutically active substance and 10-80 weight percent of a matrix, in which the matrix consists of 31-100% xanthan gum. Although Calanchi, et al. suggest combining xanthan gum with other natural or synthetic polymers, such as polymers which hydrate and dissolve in water, e.g., methyl cellulose, hydroxyethyl cellulose, or polymers having pH dependent solubility, or polymers hydrating and dissolving slowly in water, such as hydroxypropylmethyl cellulose; however, no one heretofore not, even Calanchi, et al. contemplate or suggest that in certain concentrations the xanthan gum and the hydroxypropylmethyl cellulose exhibit a synergistic effect, thereby forming a pharmaceutical carrier have significantly improved sustained release properties. This is an aspect of the present invention which the present inventors have found.
Moreover, the present invention fulfills an important need in the pharmaceutical arts. When cellulose ethers as well as hydrocolloids are used as carriers in controlled release formulations, they are usually present in high concentrations and they are a major constituent of the tablet. Unfortunately, high polymer content can adversely affect the tableting properties when prepared as dry blends and can cause difficulties when the wet granulation technique is used to form granules. Ideally, many of these problem would be alleviated if the sustained release carrier were present in lower concentrations, as this would allow the tablet size to remain small, permit it to be manageable for ingestion as well as allow addition of excipient thereto which improves compressibility thereof. Moreover, a low concentration of a sustained release carrier would enhance the ability to formulate drugs in compositions wherein the drug is present in high doses, e.g., in excess of 500 mg per tablet. The present invention by combining a hydrocolloid with a cellulose ether achieves this objective.
For a sustained release carrier to function well, the cellulose ether or hydrocolloid therein must hydrate quickly when it comes in contact with water to form a gel and control the release of the drug. However, the gel that is formed must be firm to prevent fast dissolution or erosion of the protective gel. Unfortunately, many polymers of cellulose ether, including various form of hydroxypropylmethyl cellulose, form firm gels but do not hydrate quickly enough to be useful as carrier. To date, only the Methocel K version of hydroxypropylmethyl cellulose has been used as a carrier in many pharmaceutical compositions, but in many cases, high concentrations thereof must be used. On the other hand, hydrocolloids, such as xanthan gum, are hydrophilic and thus hydrate very quickly. But they cannot form a strong gel, causing erosion or dissolution of gel around the tablet, thereby requiring high concentrations of such polymers to control the release. The present inventors have found, however that a synergistic combination of hydrocolloids and cellulose ether overcomes this problem, and permits the formulator to tailor the release profile for a particular drug.
Accordingly, the present invention is directed to a sustained release pharmaceutical tablet for administering to a host, said tablet comprising a pharmaceutically effective amount of an active ingredient, and a sustained release carrier, said carrier comprising a hydrocolloid selected from the group consisting of xanthan gum, guar gum and alginic acid or a pharmaceutically acceptable salt thereof and (b) a cellulose ether, said hydrocolloid and cellulose ether being present in a synergistic effective amount sufficient to retard the release of said pharmaceutically active ingredient, said carrier being present in less than about 40% by weight of said tablet, said hydrocolloid being present in an amount ranging from 0.3% to about 7.0% of said tablet, and said cellulose ether being present in an amount ranging from 3% to about 25% by weight of the tablet, with said cellulose ether being present in at least about 33% by weight of the carrier.